3rd AC21 International Research Festival
From Genes to Patients: New Perspectives on Personalised Medicines
Wednesday 5th July 2006
Jan Dumanski Podcast
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My name is Jan Dumanski and I’m Professor of Genetics at the University of Alabama, Birmingham,
in the US and I’m also a Professor of Experimental Pathology at the Uppsala University in Sweden.
I’m Donald Singer, Professor of Clinical Pharmacology and Therapeutics at the Graduate Medical
School, University of Warwick. Professor Dumanski has been here today speaking at an international
symposium discussing better approaches to personalising medicines. This is part of an international
research festival, with 10 events, hosted by Warwick University on behalf of the international AC 21
Consortium, of 25 universities. From Sydney to Nagoya, and Beijing to the USA.
DS: Professor Dumanski, what lead to your interest in genetics?
JD: I started to work on a cancer-related project during my PhD and cancer is a genetic disorder.
Through cancer genetics I became interested generally in genetics.
DS: What explains your fascination in Chromosome 22?
JD: This was the chromosome with which I started as a graduate student in Sweden, in Stockholm
and it is a very interesting part of our genome because it’s very well studied very gene rich and is
involved in a wide range of different disorders, including cancer. It also served as a pilot project for
the whole human genome. Much of the work which was earlier on done on Chromosome 22 became
scaled up later to the whole genome. It’s a very intriguing chromosome.
DS: In terms of how we can understand genetic variability, there’s a lot of interest in SNP variations,
but you are particularly interested in CNP variations. Can you explain what the difference between
these two terms is?
JD: So SNP, as the name suggests, is a Singular Nucleotide Polymorphism. This is a very tiny
change in one letter in our genetic code. CNP is the copy number change. People are calling it also
a segmental copy number change. This involves a gain or a deletion of a larger segment of our
genome. That means, sometimes for very large and sometimes very small parts of our genome, you
can have 3 copies or zero or 1 copy of a particular segment. I believe that before we go very deeply
into the analysis of 500,000 or 300,000 SNPs for the whole human genome, we have to have a good
knowledge of what’s going on with the copy number changes. The two levels of analysis are two
sides of the same coin and we can not study one without studying the other. I believe that so far a
little bit too much resource has gone into analysis of SNPs compared to how much has been done at
the CNP level. So that’s the answer to why I’m interested in CNPs, trying to reach the same level of
analysis as SNPs have.
DS: Regarding the CNP variation, can you expand on to what extent there can be this amplification,
how many copies you might get and give some examples, for example of HIV, cancer-related
implications of this variation?
Research Festival website:
http://go.warwick.ac.uk/research_fest
3rd AC21 International Research Festival
JD: It very much depends on what we’re looking at, whether, for example, we are looking at the
normal DNA, the normal human genome from the normal cells, or are we looking at the genome of a
cancer cell. In the normal human genome, we have so far not seen changes which go beyond 4
copies of a certain locus or zero copies of a certain locus. But, when we are looking at the cancer
cells, amplifications exceeding 10 copies are frequent and you can see them very easily. Thich is an
illustration of a genetic de-regulation of the cancer cell.
DS: In relation to HIV and over- or under-availability of these copies, is there any important
significance for this?
JD: Yes, so one of the very good examples of the involvement of the copy number changes in a
human disorder, is the susceptibility or protection against the HIV infection, involving either receptor
CCR5, receptor gene copy number, or the copy number of the ligand, which means the molecule that
is binding to that receptor, which can be present up to 20 copies in a T-cell. The importance of this is
that in order to develop efficient vaccines against HIV for instance, we have to know what is the
genotype of the person who is vaccinated with the drug, because the effect depending on the
genotype might be totally different. If you are protected you will see a very poor response to a good
vaccine and vice-versa. So genotype information is very important, for instance, for the development
of efficient HIV vaccines.
DS: Are there any particular cancers where there’s information known about deletions being
important in families where there’s increased risk of cancer?
JD: There is a large number of different tumour syndromes which are pre-disposing for cancers.
This pre-disposition is usually mediated by a deletion of a tumour suppressor gene, which is predisposing for that disorder. The technology which we are using today when we are analysing the
whole human genome on a single chip, would lead to a very rapid identification of most of today’s
known tumour suppressor genes or growth genes. This illustrates the power of the method. So,
cancer is one of the areas where deletions or amplifications are very important and we should say
here, that the finding and characterisation of these aberrations is providing an opportunity for the
development of new drugs. An instance is the very successful story of Gleevec (imatinib mesylate),
a drug which targets the activated Bcr-Abl tyrosine kinase gene. [Imatinib mesylate specifically
inhibits the proliferation of Bcr-Abl-expressing cells and thus is a prime example of gene product
targeted therapy, in this case of value in the treatment of the white blood cell cancer chronic
myelogenous leukemia]. Similar drugs might be developed towards the blocking of the receptors of
other molecules which are amplified, for instance, in cancer cells. Study of the amplifications and
deletions in both normal and cancer cells is very important knowledge.
DS: Finally, what are the practical and economic implications of taking this technology from the lab
into the clinic?
JD: These techniques are usually very costly. Whichever technique we are using today, the costs
are considerable and one of the goals is to decrease these costs dramatically so that we can apply
these analyses in diagnostics, but also for more efficient drug discovery. The goal is to reduce the
costs by 10-fold compared to the current costs involved in these studies.
DS: Thank you very much Professor Dumanski.
JD: Thank you very much.
Research Festival website:
http://go.warwick.ac.uk/research_fest